Hippo Pathway Deficiency Reverses Systolic Heart Failure Post-Infarction

Abstract

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure (HF) commonly results in mortality ¹ . The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration ² , is upregulated in human HF. We show that deletion of the Hippo pathway component Salvador ( Salv) in mouse hearts with established ischemic HF after myocardial infarction (MI) induced a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared to controls. Using TRAP (translating ribosomal affinity purification), we isolated cardiomyocyte specific translating mRNA. Hippo deficient cardiomyocytes had increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control (MQC) gene, Park2. Genetic studies indicated that Park2 was essential for heart repair suggesting a requirement for MQC in regenerating myocardium. Gene therapy with a virus encoding Salv shRNA improved heart function when delivered at the time of infarct or after ischemic HF post-MI was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.

Graphical abstract